Using dual-photon absorptiometry, Seeman et al. (1989) demonstrated reduced bone mass in the lumbar spine and perhaps in the femoral neck of premenopausal daughters of postmenopausal women with osteoporotic compression fractures. The findings suggested that genetic factors, expressed ... Using dual-photon absorptiometry, Seeman et al. (1989) demonstrated reduced bone mass in the lumbar spine and perhaps in the femoral neck of premenopausal daughters of postmenopausal women with osteoporotic compression fractures. The findings suggested that genetic factors, expressed as low peak bone mass, may have a role in the development of postmenopausal osteoporosis. Pocock et al. (1987) found in a twin study that the heritability of bone mass was approximately 90% in the lumbar spine and 70% in the femoral neck. Defects in type I collagen of the sort that may lead to osteogenesis imperfecta may produce a picture suggesting idiopathic osteoporosis (see 120150.0038). In studies of vertebral bone density (VBD) in 63 premenopausal women, aged 19 to 40 years, Armamento-Villareal et al. (1992) found a higher proportion of subjects with irregular menses (52% vs 23%, p = 0.03) and a positive family history of osteoporosis (86% vs 61%, p = 0.04) among subjects with low VBD when compared to subjects with normal bone density. They concluded that premenopausal estrogen exposure and possibly genetic predisposition, rather than environmental factors, are the major determinants of peak bone mass before menopause. Seeman et al. (1994) found that the daughters of women with hip fractures show reduced bone density, suggesting that low peak bone density is a leading factor in hip fracture.
Prockop (1998) reviewed the search for the genetic basis of osteoporosis. In a review of the genetics of osteoporosis, Giguere and Rousseau (2000) stated that twin studies had shown that genetic factors account for up to 80% of ... Prockop (1998) reviewed the search for the genetic basis of osteoporosis. In a review of the genetics of osteoporosis, Giguere and Rousseau (2000) stated that twin studies had shown that genetic factors account for up to 80% of the variance in bone mineral density. They suggested that, considering that the effect of each candidate gene is expected to be modest, discrepancies among the several allelic association studies may have arisen because different populations carry different genetic backgrounds and exposure to environmental factors. They expected that the development of population-specific at-risk profiles for osteoporosis would include genetic and environmental factors, as well as their interactions. In a review of progress in the elucidation of genetic control of susceptibility to osteoporosis, Ralston (2002) noted that BMD, ultrasound properties of bone, skeletal geometry, bone turnover, and pathogenesis of osteoporotic fracture are determined by the combined effects of several genes and environmental influences, but that occasionally osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome (259770) and the high bone mass syndrome (601884), caused by inactivating and activating mutations, respectively, in the LRP5 gene (603506). Huang and Kung (2006) reviewed the genes implicated in osteoporosis. - Association with COL1A1 Grant et al. (1996) described a novel G-to-T polymorphism in a regulatory region of the COL1A1 gene (dbSNP rs1800012; 120150.0051). They found that the polymorphism was significantly related to bone mass and osteoporotic fracture. G/T heterozygotes at the polymorphic Sp1 site (Ss) had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in 2 populations of British women, 1 from Aberdeen and 1 from London, and BMD was lower still in T/T homozygotes (ss). The unfavorable Ss and ss genotypes were overrepresented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%), equivalent to a relative risk of 2.97 (95% confidence interval 1.63-9.56) for vertebral fracture in individuals who carried the 's' allele. While the mechanisms that underlie this association remained to be defined, the COL1A1 Sp1 polymorphism appeared to be an important marker for low bone mass and vertebral fracture, raising the possibility that genotyping at this site may be of value in identifying women who are at risk of osteoporosis. The findings of Grant et al. (1996) were confirmed and extended by Uitterlinden et al. (1998). Idiopathic osteoporosis indistinguishable from involutional or postmenopausal osteoporosis beginning at an unusually early age has been described in families on the basis of specific mutations in the COL1A1 gene (120150.0038) on chromosome 17q and the COL1A2 gene (120160.0030) on chromosome 7q. Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, dbSNP rs1107946, 120150.0067; -1663indelT, dbSNP rs2412298, 120150.0068; +1245G-T, dbSNP rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding dbSNP rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains. - Association with ESR1 BMD, the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of the ESR1 gene (133430) is associated with low BMD indicated ESR1 as a candidate gene for osteoporosis. Becherini et al. (2000) genotyped 610 postmenopausal women for 3 ESR1 gene polymorphisms (intron 1 RFLPs PvuII and XbaI, and a (TA)n repeat 5-prime upstream of exon 1). Although no significant relationship between intron 1 RFLPs and BMD was observed, a statistically significant correlation between (TA)n-repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects having a low number of repeats (TA less than 15) showing the lowest BMD values. The authors observed a statistically significant difference in the mean +/- SD number of (TA)n repeats between 73 analyzed women with a vertebral fracture and the nonfracture group, equivalent to a 2.9-fold increased fracture risk in women with a low number of repeats. Becherini et al. (2000) concluded that in their large sample the (TA)n polymorphism in ESR1 accounts for part of the heritable component of BMD and may prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis. See 601769 for a discussion of contradictory findings concerning a relationship between bone mineral density and polymorphism of the vitamin D receptor. Colin et al. (2003) studied the combined influence of polymorphisms in the ESR1 and the VDR (601769) genes on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 years and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and 3 ESR1 haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. ESR1 haplotype 1 was dose-dependently associated with increased vertebral fracture risk corresponding to an odds ratio of 1.9 (95% confidence interval, 0.9-4.1) per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (p = 0.01) between ESR1 haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ESR1 haplotype 1 with vertebral fracture risk was present only in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 for heterozygous and 10.3 for homozygous carriers of ESR1 haplotype 1. These associations were independent of bone mineral density. The authors concluded that interaction between ESR1 and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density. In a study of femoral neck bone loss in 945 postmenopausal Scottish women who had not received hormone replacement therapy, Albagha et al. (2005) found that the ESR1 px haplotype was associated with reduced femoral neck BMD and increased rates of femoral neck bone loss. - Association with IL6 Linkage studies have suggested that variation in the interleukin-6 (IL6; 147620) gene is associated with BMD and osteoporosis. - Association with RIL Association studies by Omasu et al. (2003) suggested a relationship between susceptibility to osteoporosis and genetic variation in the 5-prime flanking region of the RIL gene (603422.0001). - Association with ITGB3 Tofteng et al. (2007) analyzed the L33P polymorphism in the ITGB3 gene (173470.0006) in 9,233 randomly selected Danish individuals, of whom 267 had a hip fracture during a 25-year follow-up period. Individuals homozygous for L33P had a 2-fold greater risk of hip fracture compared to noncarriers (p = 0.02), with risk confined primarily to postmenopausal women, in whom the hazard ratio was 2.6 after adjustment for age at menopause and use of hormone replacement therapy.